PLD3 and PLD4 synthesizeS,S-BMP, a key phospholipid enabling lipid degradation in lysosomes

Abstract

SUMMARYBis(monoacylglycero)phosphate (BMP) is an abundant lysosomal phospholipid required for degradation of lipids, in particular gangliosides. Alterations in BMP levels are associated with neurodegenerative diseases. Unlike typical glycerophospholipids, lysosomal BMP has two chiral glycerol carbons in theS(rather than theR) stereo-conformation, protecting it from lysosomal degradation. How this unusual and yet crucialS,S-stereochemistry is achieved is unknown. Here we report that phospholipases D3 and D4 (PLD3 and PLD4) synthesize lysosomalS,S-BMP, with either enzyme catalyzing the critical glycerol stereo-inversion reactionin vitro. Deletion of PLD3 or PLD4 markedly reduced BMP levels in cells or in murine tissues where either enzyme is highly expressed (brain for PLD3; spleen for PLD4), leading to gangliosidosis and lysosomal abnormalities. PLD3 mutants associated with neurodegenerative diseases, including Alzheimer’s disease risk, diminished PLD3 catalytic activity. We conclude that PLD3/4 enzymes synthesize lysosomalS,S-BMP, a crucial lipid for maintaining brain health.